Designs for dose–escalation trials with quantitative responses

In a dose–escalation trial for a new drug, each successive dose is tested on a new cohort of volunteer subjects, so that if any dose produces severe adverse reactions then higher doses are not tested. However, if there are other differences between the cohorts, such as differences in environmental health factors, type of person or experimental procedure, then these differences may obscure the differences between doses. Therefore, cohorts should be fitted in the analysis, as either fixed or random effects. I suggest that, if this is done, then there are three simple principles that reduce variance (i) allocating no more than half the subjects in any cohort to any single dose; (ii) subject to safety constraints, using as many different doses as possible in each cohort; (iii) using one more cohort than the number of doses, without increasing the total number of subjects. Using these principles, I propose some new designs that conform to the safety rules of traditional dose–escalation trials while reducing the variance of the estimators of differences between the doses by a factor of two or more, for the same number of subjects. Copyright © 2009 John Wiley & Sons, Ltd.     

Re-estimating the sample size of an on-going blinded trial based on the method of randomization block sums

We extend a method we had previously described (Statist. Med. 2005) to estimate the within-group variance of a continuous endpoint without breaking the blind in a randomized clinical trial. Specifically, we: (a) explain how the method may be used for a wider set of designs than we had previously indicated; (b) obtain a within-group, covariate-adjusted, blinded variance estimator; (c) illustrate use of the method for sample size re-estimation; and (d) describe a procedure to determine whether or not the blinded variance estimator works well not just on average but for the data set at hand. The proposed method is simple to use and makes no additional assumptions than is made for unblinded analysis. Simulations show that for realistic sample sizes there is virtually no inflation in the Type I error rate. When weighing the burden imposed by interim unblinded re-estimation with the loss in precision with blinded re-estimation, it may be advantageous for some trials to use the blinded method.     

患者自测腋温在临床运用的研究

目的：了解目前临床上患者自测腋温与护士按教科书规定的规范化测量腋温的测量结果是否有差异,讨论可否将自测腋温应用于临床。方法：对同一患者,在最接近的时问内先后采取让患者自测腋温与护士规范化测量腋温各-次,合计782例,采用统计描述及配对样本t检验的统计方法对结果进行处理。结果：临床患者自测腋温所测得的体温值与护士按教科书规定的规范化测量腋温所测得的体温值差异无统计学意义。结论：临床让患者自测体温的方法具有可行性、实用性。建议将体温测量作为临床护理健康教育内容之一,同时加强临床腋温操作的监督管理。     

临床路径应用于胆囊结石腹腔镜胆囊切除术的变异分析与管理

目的分析临床路径应用于胆囊结石腹腔镜胆囊切除术的变异情况及管理措施。方法选取我院实施胆囊结石腹腔镜切除术临床路径患者92例,详细记录并说明变异情况,按不同评价方法对变异进行分析。结果正性变异发生率为73．91％,负性变异发生率为26．09％;疾病转归造成的变异发生率为56．52％,医务人员造成的变异发生率为33．70％,医院系统造成的变异发生率为6．52％,病人需求所造成的变异发生率为3．26％：可控变异发生率为43．22％,不可控变异发生率为56．78％。结论通过对胆囊结石腹腔镜胆囊切除术临床路径变异情况的分析,有利于医疗质量持续改进,并为科学制定临床路径提供依据。     

野战运血车在长途血液运输中的性能测试

目的：测试野战运血车在不同温度案件下的保温、制冷和油耗等性能,为保障战争或突发情况下血液运输的安全、可靠提供基本依据.方法：2台野战运血车按最大容量装载血液,一辆车装红细胞悬液．另一辆装冰冻血浆。在35℃以上和25℃以下运行的外环境下,分别测试其无动力源情况下维持或制冷至冷冻或冷藏温度的时间和油耗。结果：在上述的条件下,野战运血车的保温时间为1．5—7h,制冷时间为15-138min。内置制冷系统的一箱油（20L）维持的运行时间为5-7h.结论：在长途运血时,如不能确保运血车的制冷系统正常运行,且运输时间超过一定的时限．则必须考虑多种保温方法联合使用     

高温作业工人197名心电图分析

目的了解高温作业工人心电图的改变。方法对197名高温作业工人心电图检查结果与对照人群进行比较。结果高温作业工人心电图改变异常率为44.67％,明显高于对照组的25．63％,差异有统计学意义（P〈0.01）,主要改变为窦性心动过缓、窦性心律不齐。结论接触高温对心脏产生一定影响,应加强防护措施。     

Intravascular Temperature Control System to Maintain Normothermia in Organ Donors

Introduction  Temperature regulation in humans is controlled by the hypothalamus. After death by neurological criteria, the hypothalamus ceases to function and poikilothermia ensues. Preservation of normothermia in those patients destined to become organ donors is an important part of maintaining the normal physiology of the organs and organ systems. Typical means of achieving normothermia include increasing the temperature of the ambient air, infrared warming lights, instillation of warmed intravenous fluids, and warm air or water blankets. Methods  In this prospective case series of five organ donors, we used an intravascular temperature modulation catheter (Alsius, Irvine, CA) to maintain normothermia in organ donors declared dead by neurological criteria. Data on accuracy of temperature maintenance at 37°C and nursing ease of use were collected. Results  This intravascular temperature modulation catheter provided an accurate method of temperature regulation in brain death donor and easier to use from a nursing workload perspective. Conclusions  Intravascular warming is a viable method for the maintenance of normothermia in organ donors. The experience here provides some insight into the ability of these devices to warm patients in other clinical situations. Originally presented at the Neurocritical Care Society, 2nd Annual Meeting, San Diego, CA, 2004.     

Footprint of greenhouse forcing in daily temperature variability

Changes in mean climatic conditions will affect natural and societal systems profoundly under continued anthropogenic global warming. Changes in the high-frequency variability of temperature exert additional pressures, yet the effect of greenhouse forcing thereon has not been fully assessed or identified in observational data. Here, we show that the intramonthly variability of daily surface temperature changes with distinct global patterns as greenhouse gas concentrations rise. In both reanalyses of historical observations and state-of-the-art projections, variability increases at low to mid latitudes and decreases at northern mid to high latitudes with enhanced greenhouse forcing. These latitudinally polarized daily variability changes are identified from internal climate variability using a recently developed signal-to-noise-maximizing pattern-filtering technique. Analysis of a multimodel ensemble from the Coupled Model Intercomparison Project Phase 6 shows that these changes are attributable to enhanced greenhouse forcing. By the end of the century under a business-as-usual emissions scenario, daily temperature variability would continue to increase by up to a further 100% at low latitudes and decrease by 40% at northern high latitudes. Alternative scenarios demonstrate that these changes would be limited by mitigation of greenhouse gases. Moreover, global changes in daily variability exhibit strong covariation with warming across climate models, suggesting that the equilibrium climate sensitivity will also play a role in determining the extent of future variability changes. This global response of the high-frequency climate system to enhanced greenhouse forcing is likely to have strong and unequal effects on societies, economies, and ecosystems if mitigation and protection measures are not taken.

The effect of anthropogenic greenhouse gas emissions on mean climatic conditions is well understood. Theory, observational, and modeling work all demonstrate that average temperatures increase as a result of elevated greenhouse gas concentrations (1). However, it is also of considerable importance to natural and human systems whether changes in the temporal variability of climatic conditions have accompanied historical global warming and whether they will do so in the future (2–5). A more variable climate implies greater uncertainty and greater frequency of extremes, both of which constitute more damaging conditions.The variability of climate from one year to the next has received considerable attention. Large-scale climatic oscillations, such as the El Niño Southern Oscillation and the Indian Ocean Dipole, are dominant determinants of interannual variability (6–8) and have been shown to exhibit more frequent extremes under enhanced greenhouse forcing within comprehensive climate models (9–11), results that are supported by paleoclimatic evidence (12). Identifying a response in interannual temperature variability has been less conclusive. Some studies have attributed recent summer temperature extremes to greater interannual variability, both regionally (13) and globally (14), but there is still debate as to the extent of the role of interannual variability (15–17). Some regional trends in interannual temperature variability have been identified (17–21), but there is no consensus between observations and climate models (22).Here, we focus on variability of temperature at a higher frequency (daily), which a growing body of econometric literature has identified as an important determinant of societal outcomes, including human health (23–27), agriculture (28–30), and economic growth (31). The effect of enhanced greenhouse gas concentrations on the daily variability of temperature is therefore of wide societal importance and a critical component of the impact of anthropogenic climate change.Decreases in daily temperature variability at northern mid to high latitudes have been detected in observations (32–34) and agree well with predictions from comprehensive climate models (34–36) and physical reasoning (34, 35). Previous generations of climate models have also suggested that daily variability may increase during European summer (37) and across the tropics (36, 38), but these predictions have not yet been detected in observations or confirmed in state-of-the art climate models. This paper unifies these works by presenting a global analysis of changes in subseasonal, daily temperature variability under enhanced greenhouse forcing in both reanalyses of historical observations (National Oceanographic and Atmospheric Administration [NOAA] 20th Century Reanalysis Version 3 and the European Centre for Medium-Range Weather Forecasts Reanalysis 5 [ERA-5]) and the latest generation of comprehensive climate models (Coupled Model Intercomparison Project phase 6 [CMIP-6]). Daily temperature variability refers to the intramonthly SD of daily surface temperature from hereon. We consider changes in daily variability in boreal winter (“DJF”), boreal summer (“JJA”), and across the year (“annual”) to both assess the season specific mechanisms identified in previous work and to provide an aggregated overview of variability changes.     

Variance inflation in sequential calculations of body surface area, plasma volume, and prostate-specific antigen mass

OBJECTIVE

To assess the magnitude of variability among 11 formulae for human body surface area (BSA) and then among eight for plasma volume (PV), as used to represent physiological indices for body metabolism, drug dosages and body fluid management, and to evaluate the potential cumulative effect of variance inflation with prostate‐specific antigen (PSA) mass as an endpoint.

PATIENTS AND METHODS

In 3020 men undergoing robotic radical prostatectomy (RRP) at the Vattikuti Urology Institute between 2001 and 2008, the variation in BSA and PV formulae was calculated, as well as PSA mass, using analysis of variance (anova ), Bland‐Altman plots, linear regression, and correlation analyses.

RESULTS

For estimating BSA, anova indicated significant variance among the 11 formulae used (P < 0.001) with a between‐groups variance of 5.45. Bland‐Altman plots reported bias when the Dubois formula was compared to other BSA formulae. Furthermore the anova for PV, with BSA as a predictor, indicated significant variance among the eight formulae used (P < 0.001), with a mean between‐group variance of 444.4 and a mean inflation factor of 81.5. Scatter plots between one PV formula (Boer) and others had a good linear fit. For PSA mass, anova indicated significant variance (P < 0.001) using PV as a predictor, with a mean between‐group variance of 16 799.6 and a mean variance inflation factor of 37.8.

CONCLUSIONS

There is significant variation in the BSA calculated by commonly used formulae. This variation is carried over and further magnified in the sequential calculation of PV and PSA mass. Hence arbitrary selection of BSA and PV formulae is likely to affect inferences.